Abstract
ObjectiveMechanical ventilation (MV) is a life saving intervention for patients with respiratory failure. Even after 6 hours of MV, diaphragm atrophy and dysfunction (collectively referred to as ventilator-induced diaphragmatic dysfunction, VIDD) occurs in concert with a blunted blood flow and oxygen delivery. The regulation of hypoxia sensitive factors (i.e. hypoxia inducible factor 1α, 2α (HIF-1α,–2α), vascular endothelial growth factor (VEGF)) and angio-neogenetic factors (angiopoietin 1–3, Ang) might contribute to reactive and compensatory alterations in diaphragm muscle.MethodsMale Wistar rats (n = 8) were ventilated for 24 hours or directly sacrificed (n = 8), diaphragm and mixed gastrocnemius muscle tissue was removed. Quantitative real time PCR and western blot analyses were performed to detect changes in angio-neogenetic factors and inflammatory markers. Tissues were stained using Isolectin (IB 4) to determine capillarity and calculate the capillary/fiber ratio.ResultsMV resulted in up-regulation of Ang 2 and HIF-1α mRNA in both diaphragm and gastrocnemius, while VEGF mRNA was down-regulated in both tissues. HIF-2α mRNA was reduced in both tissues, while GLUT 4 mRNA was increased in gastrocnemius and reduced in diaphragm samples. Protein levels of VEGF, HIF-1α, -2α and 4 did not change significantly. Additionally, inflammatory cytokine mRNA (Interleukin (IL)-6, IL-1β and TNF α) were elevated in diaphragm tissue.ConclusionThe results demonstrate that 24 hrs of MV and the associated limb disuse induce an up-regulation of angio-neogenetic factors that are connected to HIF-1α. Changes in HIF-1α expression may be due to several interactions occurring during MV.
Highlights
Mechanical ventilation (MV) is a life-saving intervention in patients with respiratory insufficiency
In order to investigate the result of MV on hypoxia-induced transcription factors, we measured vascular endothelial growth factor (VEGF) and hypoxia inducible factor (HIF)-1a mRNA expression
A significant up-regulation of HIF-1a mRNA was found in both diaphragm and gastrocnemius compared to control after MV
Summary
Mechanical ventilation (MV) is a life-saving intervention in patients with respiratory insufficiency. Several factors regulate the tissue response to altered oxygen supply and/or changes in blood flow in order to initiate changes in blood vessel architecture. The hypoxia inducible factor (HIF)-1a protein is a heterodimer consisting of O2 sensitive subunits and is expressed in all mammalian cell types [5,6]. HIF-1a acts as a transcription factor for a variety of genes, including vascular endothelial growth factor (VEGF), a powerful modulator of vessel neogenesis in response to hypoxia [10]. In concert with VEGF, vasculogenesis is regulated, in part, by the angiopoietin (Ang) family transcription factors that are expressed in different isoforms (Ang 1–4) [11,12]. Capillary sprouting has been described in the presence of VEGF, while in its absence a capillary regression is initiated [11]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have